Morphine affects brain activity and volumes in preterms: An observational multi-center study.

OBJECTIVE: We hypothesized that morphine has a depressing effect on early brain activity, assessed using quantitative aEEG/EEG parameter and depressed activity will be associated with brain volumes at term in extremely preterm infants. STUDY DESIGN: 174 preterm infants were enrolled in 3 European tertiary NICUs (mean GA:26 ± 1wks) and monitored during the first 72 h after birth with continuous 2 channel aEEG. Six epochs of aEEG recordings were selected and minimum amplitude of aEEG (min aEEG), percentage of time amplitude <5 µV (% of time < 5 µV), spontaneous activity transients (SATrate) and interSAT interval (ISI) were calculated. For infants receiving morphine, the cumulative morphine dosage was calculated. In a subgroup of 58 infants, good quality MRI at term equivalent age (TEA) and the cumulative morphine dose until TEA were available. The effects of morphine administration and cumulative dose on aEEG/EEG measures and on brain volumes were investigated. RESULTS: Morphine administration had a significant effect on all quantitative aEEG/EEG measures, causing depression of early brain activity [longer ISI (ß 2.900), reduced SAT rate (ß -1.386), decreased min aEEG (ß -0.782), and increased % of time < 5 µV (ß 14.802)] in all epochs. A significant effect of GA and postnatal age on aEEG/EEG measures was observed. Cumulative morphine dose until TEA had a significant negative effect on total brain volume (TBV) (ß -8.066) and cerebellar volume (ß -1.080). CONCLUSIONS: Administration of sedative drugs should be considered when interpreting aEEG/EEG together with the negative dose dependent morphine impact on brain development.

Early neurophysiology and MRI in predicting neurological outcome at 9-10 years after birth asphyxia.

OBJECTIVE: To assess whether early somatosensory evoked potentials (SEP) predict long-term neurodevelopmental outcome in normothermic, full-term infants with mild to moderate neonatal encephalopathy (NE), and to compare their predictive value to already available amplitude integrated EEG (aEEG) and magnetic resonance imaging (MRI). METHODS: Fifty-six infants with post-asphyxia NE were prospectively recruited, and their SEP, aEEG and MRI data were acquired during the first five days. Follow-up continued to 9-10 years for assessment of neuromotor and neurocognitive development. We analysed SEP latency (N1 component), normality of aEEG background pattern, as well as patterns of injury on the neonatal MRI. Neurological outcome measures at 9-10 years included conventional MRI, Movement-ABC and the WISC-III NL. RESULTS: A SEP latency <50 ms during the first five days was associated with a normal neuromotor outcome (p < 0.03), and a prolonged day 3 latency was associated with lower childhood IQ (p = 0.02). The presence of multiple seizures in aEEG, as well as a moderate or severe injury on the neonatal MRI was associated with a poor neuromotor score (p = 0.03 and p < 0.01, respectively). Combination of multiple techniques improved prediction of long-term outcome compared to single modality. CONCLUSION: Early SEPs provide information that is comparable to the already available aEEG and MRI paradigms in the prediction of long-term outcome of full-term infants with mild to moderate neonatal encephalopathy. SIGNIFICANCE: The present results call for further studies using early SEP to aid early assessment of infants treated with hypothermia.

Pharmacokinetics and clinical efficacy of phenobarbital in asphyxiated newborns treated with hypothermia: a thermopharmacological approach.

BACKGROUND AND OBJECTIVES: Therapeutic hypothermia can influence the pharmacokinetics and pharmacodynamics of drugs, the discipline which is called thermopharmacology. We studied the effect of therapeutic hypothermia on the pharmacokinetics of phenobarbital in asphyxiated neonates, and the clinical efficacy and the effect of phenobarbital on the continuous amplitude-integrated electroencephalography (aEEG) in a prospective study. PATIENTS AND METHODS: Data were obtained from the prospective SHIVER study, performed in two of the ten Dutch level III neonatal intensive care units. Phenobarbital data were collected between 2008 and 2010. Newborns were eligible for inclusion if they had a gestational age of at least 36 weeks and presented with perinatal asphyxia and encephalopathy. According to protocol in both hospitals an intravenous (repeated) loading dose of phenobarbital 20 mg/kg divided in 1-2 doses was administered if seizures occurred or were suspected before or during the hypothermic phase. Phenobarbital plasma concentrations were measured in plasma using a fluorescence polarization immunoassay. aEEG was monitored continuously. RESULTS AND CONCLUSION: A one-compartmental population pharmacokinetic/pharmacodynamic model was developed using a multi-level Markov transition model. No (clinically relevant) effect of moderate therapeutic hypothermia on phenobarbital pharmacokinetics could be identified. The observed responsiveness was 66%. While we still advise an initial loading dose of 20 mg/kg, clinicians should not be reluctant to administer an additional dose of 10-20 mg/kg. An additional dose should be given before switching to a second-line anticonvulsant drug. Based on our pharmacokinetic/pharmacodynamic model, administration of phenobarbital under hypothermia seems to reduce the transition rate from a continuous normal voltage (CNV) to discontinuous normal voltage aEEG background level in hypothermic asphyxiated newborns, which may be attributed to the additional neuroprotection of phenobarbital in infants with a CNV pattern.

Effect of the "InSurE" procedure on cerebral oxygenation and electrical brain activity of the preterm infant.

BACKGROUND: In preterm infants with respiratory distress syndrome (RDS) nasal continuous positive airway pressure (nCPAP) with the "InSurE" procedure (intubation, surfactant, extubation) is increasingly used. However, its effect on cerebral oxygenation and brain function is not known. OBJECTIVE: To evaluate the effects of the "InSurE" procedure in infants with RDS on regional cerebral oxygen saturation (rScO(2)) and relative cerebral fractional tissue oxygen extraction (cFTOE) using near infrared spectroscopy and on electrical brain activity using amplitude-integrated electroencephalography (aEEG). METHODS: Sixteen infants with RDS, treated with the "InSurE" procedure, and 16 matched controls with nCPAP, were monitored for mean arterial blood pressure (MABP), arterial oxygen saturation (SaO(2)), rScO(2), cFTOE and aEEG. Ten-minute periods were selected and averaged at 120 and 20 minutes before, during the procedure and at 30 minutes, 1, 2, 6, 12 and 24 h after the start of the "InSurE" procedure. aEEG was analysed by quantitative and qualitative (Burdjalov score) methods. RESULTS: MABP was not different between groups on all time points. rScO(2) and cFTOE were comparable between groups, but there was a trend towards lower rScO(2) and higher cFTOE 30 minutes after opioid administration in the "InSurE" infants compared with controls (62% (SD 11) vs 68% (SD 10) and 0.30 (SD 0.10 ) vs 0.28 (SD 0.11), respectively). aEEG amplitudes and Burdjalov scores were significantly lower in "InSurE" infants from 30 minutes after opioid administration up to 24 h after the start of the procedure (p<0.05). CONCLUSION: In the present study, the "InSurE" procedure did not induce perturbation of cerebral oxygen delivery and extraction, whereas electrical brain activity decreased for a prolonged period of time.

[Cerebral damage due to hypoglycaemia in otherwise healthy breast-fed term infants]. / Hypoglykemische cerebrale schade bij gezonde aterme neonaten die uitsluitend borstvoeding krijgen.

Two healthy breast-fed term infants were admitted to the neonatal unit with symptomatic hypoglycaemia and seizures. In both patients, risk factors (i.e. hypothermia) and symptoms ofhypoglycaemia went unrecognised until apnoea or seizures developed. Both patients required antiepileptic medication for neonatal seizures. One patient had isolated restricted growth in head circumference in the first year of life. Follow-up at II years showed cognitive impairment and epilepsy. The other patient had normal head circumference and mild global delay in neurological development at the age of 36 months. Severe symptomatic hypoglycaemia in healthy breast-fed term infants may cause severe brain damage. Early recognition of risk factors such as hypothermia lasting more than 3 hours is essential to preventing hypoglycaemia. The presence of risk factors warrants additional bottle-feeding to maintain sufficient intake until breastfeeding is adequately established. Any uncertainty regarding the symptoms of hypoglycaemia should be investigated promptly.

Application of UL144 molecular typing to determine epidemiology of cytomegalovirus infections in preterm infants.

Sequence analysis of the UL144 gene of human cytomegalovirus (CMV) was used to investigate the epidemiology of CMV infections in preterm infants. Nosocomial transmission of CMV from congenitally infected infant to preterm twins was excluded based on distinct molecular profiles of CMV strains. Indistinguishable molecular profiles between strains from the mother and the infant indicated postnatal acquisition of CMV through breastfeeding.

Recovery of amplitude integrated electroencephalographic background patterns within 24 hours of perinatal asphyxia.

OBJECTIVE: To assess the time course of recovery of severely abnormal initial amplitude integrated electroencephalographic (aEEG) patterns (flat trace (FT), continuous low voltage (CLV), or burst suppression (BS)) in full term asphyxiated neonates, in relation to other neurophysiological and neuroimaging findings and neurodevelopmental outcome. METHODS: A total of 190 aEEGs of full term infants were reviewed. The neonates were admitted within 6 hours of birth to the neonatal intensive care unit because of perinatal asphyxia, and aEEG recording was started immediately. In all, 160 infants were included; 65 of these had an initial FT or CLV pattern and 25 an initial BS pattern. Neurodevelopmental outcome was assessed using a full neurological examination and the Griffiths' mental developmental scale. RESULTS: In the FT/CLV group, the background pattern recovered to continuous normal voltage within 24 hours in six of the 65 infants (9%). All six infants survived the neonatal period; one had a severe disability, and five were normal at follow up. In the BS group, the background pattern improved to normal voltage in 12 of the 25 infants (48%) within 24 hours. Of these infants, one died, five survived with moderate to severe disability, two with mild disability, and four were normal. The patients who did not recover within 24 hours either died in the neonatal period or survived with a severe disability. CONCLUSION: In this study there was a small group of infants who presented with a severely abnormal aEEG background pattern within six hours of birth, but who achieved recovery to a continuous normal background pattern within the first 24 hours. Sixty one percent of these infants survived without, or with a mild, disability.

Midazolam and amplitude-integrated EEG in asphyxiated full-term neonates.

AIM: In the present, prospective study, the relation between the levels of midazolam, its two active metabolites--1-hydroxy-midazolam (OH-midazolam) and 1-hydroxy-midazolam-glucuronide (glu-midazolam)--and the aEEG were examined. PATIENTS AND METHODS: Fifteen full-term neonates with seizures due to hypoxic-ischaemic encephalopathy admitted to our NICU were included. Midazolam (loading dose 0.05 mg/kg in 10 min, maintenance dose 0.15 mg/kg/h) was used as an add-on anti-convulsant after phenobarbital and lidocaine because of continuing seizures. Amplitude-integrated EEG background pattern was scored at the start of midazolam and at the time of blood sampling as continuous normal voltage (CNV), discontinuous normal voltage (DNV), burst suppression (BS), continuous low voltage (CLV) or flat trace (FT). Serum levels of midazolam, OH-midazolam and glu-midazolam were measured at least 8 h after the start with HPLC. RESULTS: In 11/15 patients, seizures were abolished with the addition of midazolam. In the remaining patients, seizure frequency was reduced in one and unchanged in three. Amplitude-integrated EEG background pattern at the start of midazolam was CNV in two, DNV in six, BS in five and CLV in two. Moderate, temporary suppression of the aEEG background pattern lasting less than 2 h was seen in four neonates. Amplitude-integrated EEG at midazolam sampling was CNV in two, DNV in seven, CLV in two and FT in four. Serum levels of midazolam ranged from 0.10 to 1.76 mg/l, OH-midazolam from 0.05 to 0.28 mg/l and glu-midazolam from 0.85 to 4.36 mg/l. CONCLUSIONS: A brief and moderate suppression of the aEEG background pattern immediately after midazolam was seen in four neonates for less than 2 h. Suppression at a later time point, i.e. after more than 8 h of midazolam infusion, was demonstrated almost exclusively in neonates with a poor background pattern, and therefore these patterns appear to be determined mainly by the severity of hypoxic-ischaemic encephalopathy.

Effects of magnesium sulphate on amplitude-integrated continuous EEG in asphyxiated term neonates.

UNLABELLED: In this study it is hypothesized that magnesium sulphate in asphyxiated full-term neonates could lead to a gradual improvement in background pattern of the amplitude integrated EEG (aEEG), an early marker of hypoxic-ischaemic brain injury. In a double-blind, randomized, controlled pilot study of 22 asphyxiated full-term neonates 8 received magnesium sulphate, reaching serum Mg2+ levels of 2.5 mmol/L. Magnesium sulphate had no immediate effect on aEEG-patterns. At 12 h of age, aEEG was more depressed compared with aEEG at 3 h in 6 of the 8 magnesium-treated neonates, and in 3 of the 14 placebo-treated neonates (Mg2+ vs placebo: p < 0.05, Mann-Whitney). No further significant changes in aEEG were seen between 12 and 24 h. Outcome was unfavourable in 4 of the 8 magnesium-treated neonates, and in 8 of the 14 placebo-treated neonates. CONCLUSION: Magnesium sulphate did not have a positive effect on aEEG patterns in this small group of asphyxiated term neonates.

Glutamate in cerebral tissue of asphyxiated neonates during the first week of life demonstrated in vivo using proton magnetic resonance spectroscopy.

We tested the hypothesis that glutamate (Glx) levels as demonstrated by proton magnetic resonance spectroscopy ((1)H-MRS) are elevated in brain tissue of neonates with severe hypoxic-ischemic encephalopathy (HIE). Studies were performed in 26 neonates (median gestational age 40.5 weeks, range 36.7-42.4 weeks; median birth weight 3,360 g, range 2,180-4,200 g). The median postnatal age at the time of testing was 2.5 days (range 1-7 days). HIE was scored according to Sarnat as grade I (n = 4), grade II (n = 15) or grade III (n = 7). Results for neonates with mild to moderate HIE (group 1) were compared to those with severe HIE (group 2). After magnetic resonance imaging, (1)H-MRS was performed in a single volume of interest including the basal ganglia. An echo time of 31 ms was used. After curve-fitting procedures, peak area ratios of different brain metabolites were calculated. The median total Glx/N-acetylaspartate ratio was 1.21 (range 0.64-3.25) in group 1 versus 1.55 (range 1.10-2.75) in group 2 (p = 0.035). The median total Glx/choline ratio was 1.33 (range 0.71-2.52) in group 1 versus 2.14 (range 1.21-3.55) in group 2 (p = 0.019). We concluded that during the first days of life, Glx was elevated in the basal ganglia of neonates with severe HIE.

Amplitude integrated EEG 3 and 6 hours after birth in full term neonates with hypoxic-ischaemic encephalopathy.

AIM: To assess the prognostic value of amplitude integrated EEG (aEEG) 3 and 6 hours after birth. METHODS: Seventy three term, asphyxiated infants were studied (from two different centres), using the Cerebral Function Monitor (CFM Lectromed). The different aEEG tracings were compared using pattern recognition (flat tracing mainly isoelectric (FT); continuous extremely low voltage (CLV); burst-suppression (BS); discontinuous normal voltage (DNV); continuous normal voltage (CNV)) with subsequent outcome. RESULTS: Sixty eight infants were followed up for more than 12 months (range 12 months to 6 years). Twenty one out of 68 infants (31%) showed a change in pattern from 3 to 6 hours, but this was only significant in five cases (24%). In three this changed from BS to CNV with a normal outcome. One infant showed a change in pattern from CNV to FT and had a major handicap at follow up. Another infant showed a change in pattern from DNV to BS, and developed a major handicap at follow up. The other 16 infants did not have any significant changes in pattern: 11 infants had CLV, BS, or FT at 3 and 6 hours and died (n = 9) in the neonatal period or developed a major handicap (n = 2). Five infants had a CNV or DNV pattern at 3 and 6 hours, with a normal outcome. The sensitivity and specificity of BS, together with FT and CLV, for poor outcome at 3 hours was 0.85 and 0.77, respectively; at 6 hours 0.91 and 0.86, respectively. The positive predictive value (PPV) was 78% and the negative predictive value (NPV) 84% 3 hours after birth. At 6 hours the PPV was 86% and the NPV was 91%. CONCLUSION: aEEG could be very useful for selecting those infants who might benefit from intervention after birth asphyxia.

[Hypertonic dehydration in "silent" malnutrition of breast-fed infants]. / Hypertone dehydratie bij 'stille' ondervoeding aan de borst.

Two firstborn, breast-fed infants (delivery at home) were admitted to the hospital in a critical state of hypernatraemic dehydration. Case 1, a boy aged 13 days, had suffered 1220 g loss of weight since birth (31%), his serum sodium concentration was 180 mmol/l. Case 2, a girl aged 7 days, had lost 610 g since birth (18%); her serum sodium level was 159 mmol/l. In both cases poor professional support of lactation and lack of weight control had resulted in unnoticed severe malnutrition. After slow rehydration recovery was uneventful. Closer monitoring of babies' weight, e.g. twice a week, is advocated especially for breast-fed firstborns in the early weeks of life.

Early cerebral proton MRS and neurodevelopmental outcome in infants with cystic leukomalacia.

The present study tested the hypothesis that proton magnetic resonance spectroscopy (1H-MRS) predicted neurodevelopmental outcome in infants with cystic leukomalacia (CL). Nineteen infants with CL (grade 2, N = 7; grade 3, N = 7; grade 4, N = 5), graded according to the authors' classification, were examined at corrected ages of mean 1.5 +/- 2.1 SD weeks. 1H-MRS of the basal ganglia and the periventricular white matter was performed. Two infants died, 16 had an adverse neurodevelopmental outcome and one was normal at follow-up. N-acetylaspartate (NAA):choline (Cho) ratios were mean 1.12 +/- 0.19 (SD) (grade 2), mean 0.95 +/- 0.11 (SD) (grade 3), and mean 0.71 +/- 0.13 (SD) (grade 4). These differences are significant (P < 0.01, ANOVA). NAA:Cho ratios showed a positive correlation with developmental quotient (DQ) at the age of > or = 1 year (P < 0.05). In 13 infants lactate (Lac) was found. Lac:NAA ratios showed a negative correlation with NAA:Cho ratios, but not with DQ. We conclude that a low NAA:Cho ratio predicted a poor outcome, whereas some infants developed unfavourably despite a normal NAA:Cho ratio. We speculate that partial volume effects might explain this observation.

Predictive value of early neuroimaging, pulsed Doppler and neurophysiology in full term infants with hypoxic-ischaemic encephalopathy.

To evaluate their prognostic value, five different non-invasive techniques were used on 34 full term infants with hypoxic-ischaemic encephalopathy (HIE) within six hours of delivery. Cranial ultrasonography, the resistance index (RI) of the middle cerebral artery obtained with Doppler ultrasonography, somatosensory evoked potentials (SEPs), visual evoked potentials (VEPs) and the cerebral function monitor (CFM) were used. According to the criteria of Sarnat, 11 infants developed mild, seven moderate, and 16 severe encephalopathy. The CFM had the highest positive (PPV 84.2%) and negative predictive value (NPV 91.7%). All but one of the infants with a continuous pattern had a good outcome. The CFM of 11 cases with a suppression-burst pattern changed to a continuous pattern over 24 to 48 hours in four infants, and was associated with a normal outcome in three. All five cases with an isoelectric CFM died. The SEPs also provided useful information (PPV 81.8%; NPV 91.7%). VEPs were often delayed during the first hours or life and did not carry a poor prognosis in five of 14 cases (PPV 77.3%). Both ultrasonography and Doppler RI were of little value, as they were almost always normal at this early stage. In 34 full term infants with HIE, studied within 6 hours of life, the CFM and SEPs provided the most useful information about the expected course of encephalopathy and subsequent neurodevelopmental outcome.

Evaluation of the Cerebro Trac 2500 for monitoring of cerebral function in the neonatal intensive care.

Assessment of brain function is important in predicting long term outcome in sick neonates thus stimulating increasing interest in methods of cerebral surveillance. A report using the Cerebro Trac 2500 in adult intensive care suggested this monitor may provide more information about ongoing cerebral activity than the Cerebral Function Monitor (CFM). Simultaneous recordings in a cross-section of the neonatal population were obtained with multichannel EEG monitor, CFM and Cerebro Trac. Both conventional EEG and CFM determined changes in sleep states and background activity. Seizures of greater than 30 seconds duration were detected by both analyzing monitors, although shorter duration transients were not apparent. Despite the apparent similarity in fixed filters in both CFM and Cerebro Trac, the Cerebro Trac seemed to filter out the lower frequencies that can predominate in the neonatal EEG. The Cerebro Trac did not confer any advantage over the CFM for neonatal cerebral surveillance.